Cocaine withdrawal enhances long-term potentiation induced by corticotropin-releasing factor at central amygdala glutamatergic synapses via CRF, NMDA receptors and PKA.
Cocaine withdrawal enhances long-term potentiation induced by corticotropin-releasing factor at central amygdala glutamatergic synapses via CRF, NMDA receptors and PKA.
复制标题
可卡因戒断可通过 CRF、NMDA 受体和 PKA 增强中央杏仁核谷氨酸突触促肾上腺皮质激素释放因子诱导的长期增强作用。
DOI：
10.1111/j.1460-9568.2006.05049.x
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Shinnick-Gallagher,Patricia
中科院分区：
文献类型：
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作者：
Pollandt,Sebastian;Liu,Jie;Orozco-Cabal,Luis;Grigoriadis,DimitriE;Vale,WylieW;Gallagher,JoelP;Shinnick-Gallagher,Patricia
可卡因成瘾是一种持久的、反复发作的行为障碍，在这种情况下，即使在长期戒断后，压力源也会恢复对可卡因的寻求。有证据表明，与长期戒断相关的“焦虑样”行为和压力可能是由杏仁核中央核（CeA）中促肾上腺皮质激素释放因子（CRF）的增加所介导的，杏仁核是参与刺激-奖励关联编码和传递的边缘回路的一部分。在本研究中，我们描述了大鼠/人CRF在外侧杏仁核(LA) - CeA突触诱导的谷氨酸能传递的持久增强。在停止重复间歇性可卡因暴露2周后，与相应的生理盐水对照组相比，CRF诱导的长期增强（LTP）大大增强，而在短期戒断（24小时）后，两个治疗组之间没有显着差异，表明慢性可卡因长期戒断期间CRF系统发生了改变。在长期戒断后，在生理盐水和可卡因处理组中，CRF诱导的LTP依赖于CRF2、CaV2.3 （R型）钙通道的激活和通过蛋白激酶C的细胞内信号传导。停药2周后，CRF诱导的LTP增强是通过crf1受体功能增强介导的，与蛋白激酶A和所需的n -甲基- d -天冬氨酸（NMDA）受体的信号传导增加有关。因此，单细胞记录显示，长时间停止可卡因治疗后，NMDA/AMPA比率显著增加。这些结果支持crf1受体拮抗剂作为慢性可卡因戒断期间可行的治疗选择的作用，并提示CaV2.3阻滞剂是药物调节CRF系统的潜在候选药物。
Cocaine addiction is an enduring, relapsing, behavioural disorder in which stressors reinstate cocaine‐seeking even after prolonged abstinence. Evidence suggests that the ‘anxiety‐like’ behaviour and stress associated with protracted withdrawal may be mediated by increased corticotropin‐releasing factor (CRF) in the central nucleus of the amygdala (CeA), a part of the limbic circuitry engaged in the coding and transmission of stimulus–reward associations. In the present study we describe a long‐lasting potentiation of glutamatergic transmission induced at lateral amygdala (LA)‐to‐CeA synapses by rat/human CRF. After 2 weeks of withdrawal from repeated intermittent exposure to cocaine, CRF‐induced long‐term potentiation (LTP) was greatly enhanced compared to the respective saline control group while, after short‐term withdrawal (24 h), there was no significant difference between the two treatment groups, indicating alterations in CRF systems during protracted withdrawal from chronic cocaine. After prolonged withdrawal, CRF‐induced LTP was dependent on activation of CRF2, CaV2.3 (R‐type) calcium channels and intracellular signalling through protein kinase C in both saline‐ and cocaine‐treated groups. The enhanced CRF‐induced LTP after 2 weeks of withdrawal was mediated through augmented CRF1receptor function, associated with an increased signalling through protein kinase A, and requiredN‐methyl‐d‐aspartate (NMDA) receptors. Accordingly, single‐cell recordings revealed a significantly increased NMDA/AMPA ratio after prolonged withdrawal from the cocaine treatment. These results support a role for CRF1receptor antagonists as plausible treatment options during withdrawal from chronic cocaine and suggest CaV2.3 blockers as potential candidates for pharmaceutical modulation of CRF systems.